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Updated: May 29, 2025
08:12
Global Level Quantification of Histone Post-Translational Modifications in a 3D Cell Culture Model of Hepatic Tissue
Published on: May 5, 2022
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Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3
Ling Ye1, Shengqi Shen2, Qiankun Mao1
1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
Cell Reports
|February 1, 2025
Summary
Nuclear HKDC1 acts as a protein kinase, phosphorylating RBBP5 to drive hepatocellular carcinoma (HCC) cell proliferation by activating mitosis genes. Targeting this kinase activity inhibits tumor growth.
Area of Science:
- Biochemistry
- Cancer Biology
- Molecular Oncology
Background:
- Metabolic enzymes are implicated in cancer pathogenesis via canonical and noncanonical roles.
- Hexokinase domain-containing protein 1 (HKDC1) has functions beyond glucose metabolism, with its role in tumorigenesis not fully elucidated.
Purpose of the Study:
- To investigate the non-canonical functions of nuclear HKDC1 in hepatocellular carcinoma (HCC) pathogenesis.
- To elucidate the molecular mechanisms by which HKDC1 promotes HCC cell proliferation.
Main Methods:
- Demonstration of nuclear HKDC1's protein kinase activity.
- Identification of RB binding protein 5 (RBBP5) as a substrate for HKDC1 phosphorylation.
- Analysis of MLL1 complex assembly and histone H3 lysine 4 trimethylation (H3K4me3) modification.
- Assessment of the impact of targeting HKDC1 kinase activity on tumor growth.
- Correlation analysis of RBBP5 phosphorylation, HKDC1 levels, and HCC patient prognosis.
Main Results:
- Nuclear HKDC1 functions as a protein kinase, phosphorylating RBBP5 at Ser497.
- RBBP5 phosphorylation is essential for MLL1 complex assembly and subsequent H3K4me3.
- This modification leads to transcriptional activation of mitosis-related genes, promoting cell cycle progression and proliferation.
- Inhibition of HKDC1's protein kinase activity, but not its hexokinase activity, suppressed tumor growth.
- RBBP5 phosphorylation levels positively correlated with HKDC1 expression and poor prognosis in HCC patients.
Conclusions:
- HKDC1 possesses a protein kinase function that drives HCC progression through RBBP5 phosphorylation and H3K4me3 activation.
- Targeting HKDC1's kinase activity represents a potential therapeutic strategy for HCC.
- RBBP5 phosphorylation serves as a prognostic biomarker for HCC.
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